Learning new sequential stepping patterns requires striatal plasticity during the earliest phase of acquisition.

Animals including humans execute motor behavior to reach their goals. For this purpose, they must choose correct strategies according to environmental conditions and shape many parameters of their movements, including their serial order and timing. To investigate the neurobiology underlying such skills, we used a multi-sensor equipped, motor-driven running wheel with adjustable sequences of foothold pegs on which mice ran to obtain water reward. When the peg patterns changed from a familiar pattern to a new pattern, the mice had to learn and implement new locomotor strategies in order to receive reward. We found that the accuracy of stepping and the achievement of water reward improved with the new learning after changes in the peg-pattern, and c-Fos expression levels assayed after the first post-switch session were high in both dorsolateral striatum and motor cortex, relative to post-switch plateau levels. Combined in situ hybridization and immunohistochemistry of striatal sections demonstrated that both enkephalin-positive (indirect pathway) neurons and substance P-positive (direct pathway) neurons were recruited specifically after the pattern switches, as were interneurons expressing neuronal nitric oxide synthase. When we blocked N-methyl-D-aspartate (NMDA) receptors in the dorsolateral striatum by injecting the NMDA receptor antagonist, D-2-amino-5-phosphonopentanoic acid (AP5), we found delays in early post-switch improvement in performance. These findings suggest that the dorsolateral striatum is activated on detecting shifts in environment to adapt motor behavior to the new context via NMDA-dependent plasticity, and that this plasticity may underlie forming and breaking skills and habits as well as to behavioral difficulties in clinical disorders.

Standalone effects of focus mode and social comparison functions on problematic smartphone use among adolescents.

Problematic smartphone use (PSU) has been reported, particularly among adolescents. Digital interventions may be offered for preventing and reducing PSU. This study evaluated the effects of two smartphone-based interventions among adolescents. Grounded in nudge theory, the focus function allowed users to hide smartphone applications (apps) for a selected length of time, while the feedback function provided a social comparison of the smartphone use of the user and other users. In total, 305 adolescents with Android smartphones were randomly allocated to the focus-function group, feedback-function group or control group. Participants used their smartphones as usual during the two-week baseline period, followed by the one-week period of intervention app instillation and four-week period of intervention use. The primary outcome was self-reported PSU after the intervention period. The secondary outcomes were self-reported smartphone use time during weekdays and app-recorded smartphone use time and frequency. The Group × Time interaction effects showed reduced self-reported PSU in the focus-function and feedback-function groups, Cohen's d = -0.32, 95% CI [-0.63, -0.008], Cohen's d = -0.36, 95% CI [-0.66, -0.06], respectively. The app-recorded smartphone use frequency was also reduced in the focus-function and feedback-function groups, Cohen's d = -0.16, 95% CI [-0.07, -0.25], Cohen's d = -0.32, 95% CI [-0.23, -0.41], respectively. The findings suggest that both utilizing time-outs from nonessential apps and engaging in social comparison lower PSU and smartphone use frequency with small effect sizes. These functions may be noncoercive interventions for preventing and reducing PSU.

Psychometric properties of the Japanese version of the standardised assessment of personality abbreviated scale.

This study was undertaken to translate the Standardised Assessment of Personality - Abbreviated Scale (SAPAS) into Japanese and to evaluate its validity and reliability. SAPAS is one of the most rapid tools for assessing personality disorder (PD) and has excellent sensitivity and good specificity, whereas other PD assessment tools require such a significant investment of time that they are infeasible for large surveys or routine clinical practice. Customary assessment in clinical practice ideally incorporates screening for PD, as it is associated with a substantial public health burden, including premature mortality and increased health service utilization. Furthermore, PD's status as a key prognostic variable of mental disorders also drives PD screening. While SAPAS has been translated into several languages, there has been no Japanese version. Therefore, we translated SAPAS into Japanese (SAPAS-J) and evaluated its reliability and validity. Study 1 recruited undergraduates to reveal its test-retest reliability. Although its internal consistency was not high, since the intent of the original SAPAS was to assess the broad character of personality disorder with the fewest possible items, minimal correlations between items were reasonable. We tested two factorial models, the single-factor model and the higher-order-single-factor model, and the latter offered better fitting. This higher-order model contained a three-factor structure corresponding to clusters described in DSM-5. It measures general PD traits as a common higher-order latent variable comprising those factors. Correlations of SAPAS-J with the much longer PD screening questionnaire in Study 1 and depressive and anxiety symptoms in Study 2 from the general population support its validity. Although validation for the clinical use of SAPAS-J is limited, our research with non-clinical populations demonstrated sufficient validity to justify its use in the context of psychopathological analog research. Since PD is understood as a continuum, the severity of which is distributed dimensionally, the analog study recruiting from the general population and attempting to reveal psychopathological mechanisms of PD is meaningful.

Epigenetic profile of Japanese supercentenarians: a cross-sectional study.

BACKGROUND: Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline. METHODS: In this cross-sectional study, we enrolled Japanese non-centenarians (eligible participants aged 20-80 years) from the Tohoku Medical Megabank Community-Based Cohort Study and centenarians and supercentenarians (aged 101-115 years) from the Tokyo Centenarian Study and the Japanese Semi-supercentenarian Study. We assessed participants' whole-blood DNA methylation profiles and then developed sex-specific and non-specific first-generation epigenetic clocks by elastic net regression, calculated individuals' epigenetic ages, and assessed their age acceleration. We also screened for age-related CpG sites in non-centenarians by epigenome-wide linear regression analyses and ANOVA. We subsequently investigated which CpG sites in centenarians and supercentenarians had DNA methylation patterns following the age-related findings obtained from non-centenarians and which did not. We further characterised CpG sites with hypermethylation or hypomethylation in the centenarians and supercentenarians using enrichment and protein-protein interaction network analyses. FINDINGS: We enrolled 421 non-centenarians (231 [55%] women and 190 [45%] men; age range 20-78 years), recruited between May 20, 2013, and March 31, 2016, and 94 centenarians and supercentenarians (66 women [70%] and 28 [30%] men; age range 101-115 years), recruited between Jan 20, 2001, and April 17, 2018. Non-sex-specific epigenetic clock showed the highest accuracy (r=0·96) based on which centenarians and supercentenarians had negative epigenetic age acceleration. Epigenome-wide association analyses further showed that centenarians and supercentenarians had younger-than-expected epigenetic states (DNA methylation profiles similar to those of non-centenarians) for 557 CpG sites enriched in cancer-related and neuropsychiatric-related genes, whereas these individuals had advanced (or older) epigenetic states for 163 CpG sites represented by genes related to TGF-ß signalling, which is involved in anti-inflammatory responses and known to contribute to healthy ageing. INTERPRETATION: These results indicate that exceptionally healthy longevity depends not only on maintaining young epigenetic states but also on advanced states of specific epigenetic regions. FUNDING: The Japan Agency for Medical Research and Development, KDDI Research, and Keio University. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

A novel instrumented multipeg running wheel system, Step-Wheel, for monitoring and controlling complex sequential stepping in mice.

Motor control is critical in daily life as well as in artistic and athletic performance and thus is the subject of intense interest in neuroscience. Mouse models of movement disorders have proven valuable for many aspects of investigation, but adequate methods for analyzing complex motor control in mouse models have not been fully established. Here, we report the development of a novel running-wheel system that can be used to evoke simple and complex stepping patterns in mice. The stepping patterns are controlled by spatially organized pegs, which serve as footholds that can be arranged in adjustable, ladder-like configurations. The mice run as they drink water from a spout, providing reward, while the wheel turns at a constant speed. The stepping patterns of the mice can thus be controlled not only spatially, but also temporally. A voltage sensor to detect paw touches is attached to each peg, allowing precise registration of footfalls. We show that this device can be used to analyze patterns of complex motor coordination in mice. We further demonstrate that it is possible to measure patterns of neural activity with chronically implanted tetrodes as the mice engage in vigorous running bouts. We suggest that this instrumented multipeg running wheel (which we name the Step-Wheel System) can serve as an important tool in analyzing motor control and motor learning in mice.

Role of amyloidosis in determining the prognosis of dialyzed patients with rheumatoid arthritis.

The role of secondary amyloidosis in determining the prognosis of dialyzed patients with rheumatoid arthritis (RA) was examined in 22 patients with a mean age of 60.1 years included 21 renal amyloidosis. RA duration until the start of dialysis was 19.5 +/- 7.2 years and the observation period after introduction 27.1 +/- 26.4 months. Of the 14 dead cases, four died due to sepsis, three due to gastrointestinal tract bleeding, two due to congestive heart failure, and eight cases died within 5 months after starting dialysis. When comparing the eight survivors and the nine non-survivors who died within 2 years after the start of dialysis, the former patients showed significantly higher serum albumin, and lower electrocardiogram score and cardiothoracic ratios at the time of introduction to dialysis. The careful prevention and treatment of infection, cerebrovascular and/or gastrointestinal tract complications seem to be necessary to improve the prognosis of RA patients after the initiation of renal replacement therapy.